Antihypertensive n-picolyl-ethylene-diamine compositions



United States Patent 3,252,860 ANTIHYPERTENSIVE N-PICOLYL-ETHYLENE-DIAMINE COMPOSITIONS Robert Paul Mull, Florham Park, and Walter EdwardBarrett, New Vernon, N.J., assignors to Ciba Corporation, New York,N.Y., a corporation of Delaware No Drawing. Filed June 5, 1963, Ser. No.285,618 8 Claims. (Cl. 167-65) The present invention concerns a novelmethod for the treatment of hypertension, as well as pharmaceuticalcompositions capable of lowering the blood pressure inhypertensiveconditions.

A great number of pharmaceutical compositions for the treatment ofhypertension are known, which contain pure chemical substances orextracts from natural sources as the pharmacologically activeingredients. Despite this variety of compositions available to thepractitioner, the search for new antihypertensive drugs is continued andbroadened. This is mainly due to the fact, that hypertension can havemany causes, of which only a few areestablished; hypertension is,therefore, a manifestation of different disorders, which responddifferently to different treatments.

Furthermore, known compounds with antihypertensive properties havedifferent pharmacological patterns; for example, they react differentlyon the effects of pressor substances in anesthetized dogs. Thus, whilethe antihypertensive drug hydralazine decreases the pressor effects ofamphetamine, norepinephrine and angiotensin amide and reverses theeffects of epinephrine, guanethidine blocks the pressor effects ofamphetamine, but increases the responses to epinephrine, norepinephrineand hypertensin. In the same experiment, reserpine increases the pressorresponses of amphetamine, epinephrine and norepinephrine, whereasganglionic blockers useful in the treatment of severe hypertension, suchas chlorisondamine chloride, also increases the pressor effects of allthree pressor amines, but in addition, block the ganglia. These fewexamples show that there is ample room for compounds havingantihypertensive properties of different pharmacological patterns, whichcan be exploited in the treatment of various hypertensive conditions.

We have now found a new method for the treatment of hypertensiveconditions, which comprises administering to a host requiring relieffrom hypertension a composition consisting essentially of apharmacologically effective amount of an N-picolyl-ethylenediamine orespecially a pharmaceutically acceptable acid addition salt thereof, asthe active antihypertensive ingredient, together with a pharmaceuticallyacceptable carrier.

- Pharmaceutically acceptable acid addition salts of the above-mentionedN-picolyl-ethylenediamine compounds are those with inorganic acids,e.g., hydrochloric, hydrobromic, sulfuric, phosphoric acids and thelike, or with organic acids, such as organic carboxylic acids, e.g.,acetic, propionic, glycolic, succinic, maleic, fumaric, malic, tartaric,citric, benzoic, salicylic, 2-acetoxy-benzoic, nicotinic, isonicotinicacid and the like, or organic sulfonic acids, e.g., methane sulfonic,ethane sulfonic, ethane 1,2-disulfonic, Z-hydroxyethane sulfonic,p-toluene sulfonic acid and the like.

A preferred method for the treatment of hypertensive conditionscomprises administering to a host requiring resuch as the compounds ofthe formula particularly the N-(4-picolyl)-ethylenediamine, orespecially the acid addition salts of such compounds have potentantihypertensive effects. Furthermore, pharmacological tests, in whichthese compounds are administered intravenously or orally to anesthetizeddogs, reveal that the effects on the pressor responses caused by pressorsubstances are basically different from those of generally acceptedantihypertensive drugs; thus, they decrease the pressor responses ofamphetamine, epinephrine, norepinephrine and angiotensin amide. Themethod of treating antihypertensive conditions according to the presentinvention is, therefore, qualitatively different from those using knownantihypertensive drugs.

Also included within the scope of this invention are the novelpharmaceutical compositions consisting essentially of apharmacologically effective amount of an N-picolylethylenediamine orespecially a pharmaceutically acceptable acid addition salt thereof, asthe active antihypertensive ingredient, together with a pharmaceuticallyacceptable carrier. 1

Preferred compositions for the relief of hypertension are thoseconsisting essentially of a pharmacologically effective amount of acompound of the formula bining specified proportions of thepharmacologically ac-,

tive ingredient with a pharmaceutically acceptable organic or inorganiccarrier. Usually, the compositions of this invention contain at mostequal amounts of the active ingredient and the inert carrier;preferably, they aremade up to have from about 1 percent to at most 50percent by weight of the pharmacologically active ingredient in thecomposition. In compositions for oral use (e.g., tablets, capsules andthe like), the percentage, by weight is from about 5 percent to at most50 percent of active antihypertensive ingredient. In compositionsprepared for injection (e.g., solutions and the like), the percentage byweight is from about 1 percent to about 20 percent of the activeantihypertensive ingredient.

In preparing pharmaceutically acceptable dosage unit forms, any one of awide variety of preparations may be manufactured, such as tablets,capsules, pills, suppositories, solutions, suspensions and the like. Inaddition to the pharmacologically active component, there may be presentadditional substances commonly employed in the art of manufacturingpharmaceutically acceptable dosage unit compositions. These may includeexcipients, binders, fillers, lubricants, solvents, stabilizers, wettingagents, emulsifiers, buffers, and/ or other inert ingredients.

The tablet, capsule, dragee and the like provide for the oral form ofadministration. These forms may be compounded to have from about 0.01 g.to about 0.1 g., especially from about 0.015 g. to about 0.05 g., of anN-picolylethylenediamine or especially a pharmaceutically acceptableacid addition salt thereof, such as a compound of the formula orespecially a pharmaceutically acceptable acid addition salt thereof, andparticularly N-(4-picolyl)-ethylenediamine, or especially apharmaceutically acceptable acid addition salt thereof, as the activeantihypertensive ingredient, per single dosage unit, together with apharmaceutically acceptable carrier.

- The inert fillers, binders, lubricants and other materials normallyused for the manufacture of the orally applicable pharmaceuticalcompositions, e.g., tablets, capsules, dragees and the like, areemployed in their formulation. Examples of these materials are starches,e.g., corn starch, wheat starch and the like, sugars, e.g., lactose,sucrose and the like, stearic acid, magnesium stearate, calciumstearate, aluminum magnesium silicate preparations (colloidal silicapreparations), talc, tragacanth, acacia, polyethylene glycol and thelike. The quantities of these ingredients may vary widely and dependupon the characteristics and the size of the desired, orally applicableform, the method of its manufacture and the like. Encapsulation may beeffected, using, it necessary, the same excipients as those employed forthe preparation of other orally applicable forms, e.g., tablets. Anycompatible colors, approved and certified under the provisions of theFederal Food, Drug and Cosmetic Law may be used as a means ofidentification and the like.

Solutions for parenteral administration have from about 0.01 g./ml. toabout 0.1 g./ml., preferably from about 0.015 g./ ml. to about 0.05 g./ml. of an N-picolyl-ethylenediamine or especially a pharmaceuticallyacceptable acid addition salt thereof, such as a compound of the formulaor especially a pharmaceutically acceptable acid addition salt thereof,particularly the N (4-picolyl)-ethylenediamine or especially apharmaceutically acceptable acid addition salt thereof, a the activeantihypertensive ingredient, together with a pharmaceutically acceptablecarrier.

Primary solvents of the solutions for injection according to thisinvention are water, water-miscible organic solvents, such as loweralkanols, e.g., ethanol and the like, or mixtures of water andwater-miscible organic solvents, such as lower alkanols, e.g., ethanoland the like. Other ingredients are added to ensure stable solutions forinjection, for example, stabilizers, such as anti-oxidants, e.g.,thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteinehydrochloride, sodium formaldehyde sulfoxylate, mono-thioglycerol,thiosorbitol and the like, solubilizers, e.g., N,N-diethylacetamide,polyethyleneglycol, ureas, urethanes and the like, buffers and buffercombinations to maintain a preferable pH of about 7, such as, forexample, acetic acid, potassium phthalate and sodium hydroxide,potassium dihydrogen phosphate and di-sodium hydrogen phosphate,potassium dihydrogen phosphate and sodium hydroxide, acetic acid andsodium acetate, and the like, salts for making isotonic solutions, e.g.,sodium chloride and the like, or any other suitable auxiliarysubstances.

The following working examples are illustrative of the invention, butare in no way intended to limit the scope of the present invention.

Example 1 Tablets containing 0.025 g. each ofN-(4-picolyl)-ethylenediamine trihydrochloride are prepared as follows(for 800,000 tablets):

Ingredients: G.

N-(4-picolyl) ethylenediamine trihydrochloride 20,0000 Lactose USPl43,495.0 Corn starch 17,0500 Confectioners sugar 14,0000 Colloidalsilica 5,000.0 Stearic acid powder USP 2,000.0 Calcium stearate 500.0Color FD&C Yellow No. 5 5.0

Purified water, q.s.

* Equivalent to 15,0000 g. on an anhydrous basis.

The N-(4-picolyl)ethylenediamine trihydrochloride, the lactose, 12,5000g. of the corn starch, the confectioners sugar and the colloidal silicaare passed through a. No. 16 screen into a mixer and blended at lowspeed for twenty minutes. The remainder of the corn starch is suspendedin a cold solution of the color FD&C Yellow No. 5 in 5,000 ml. ofpurified water, and a paste is formed by gradually adding 20,000 ml. ofboiling purified water. The

mixed powders are granulated with the above paste, using additionalwater as'required.

The resulting moist mass is passed through a mill, using a No. 4Ascreen, placed on trays and dried at 38 C. until the moisture content isbetween 2 percent and 3 percent. The granules are broken on a millthrough a No. 16 wire mesh screen, and treated with the stearic acid andthe cal- Tablets containing 0.03 g. each ofN-(2-picolyl)-ethylenediamine trihydrochloride are prepared as follows(for 100,000 tablets):

Ingredients:

N-(Z-picolyl)-ethylenediamine trihydrochloride 3,000.000 Lactose USP17,436.875 Corn starch 2,131.250 Confectioners sugar 1,750.000 Colloidalsilica 625.000 Stearic acid powder USP 250.000 Calcium stearate 62.500Color FD&C Yellow No. 5 0.625

Purified water, q.s.

* Equivalent to 1,875.000 g. on an anhydrous basis.

The tablets, weighing 0.250 g. each, are prepared according to theprocedure described in Example 1.

In the above example, the N-(2-picolyl)-ethylenediamine trihydrochloridemay be replaced by another pharmaceutically acceptable acid additionsalt of N-(2- picolyl)-ethylenediamine or by a pharmaceuticallyacceptable acid addition salt of N-(3-picolyl)-ethylenediamine.

Example 3 Capsules containing 0.025 g. each of N-(4-picolyl)-ethylenediamine trihydrochloride are prepared as follows (for 900capsules):

Ingredients: G.

N- (4-picolyl) -ethylenediamine trihydrochloride 22.50

Lactose USP 139.50

Example 4 An injectable solution containing 0.02 g. per I111. ofN-(4-picolyl)-ethylenediamine trihydrochloride is prepared as follows(for 1,000 ml.)-

Ingredients:

N-(4-picolyl)-ethylenediamine trihydrochloride, g. 20.00 Acetic acid,glacial, ml. 8.00 Water for inpection, q.s., ml. 1000.00

The glacial acetic acid and the N-(4-picolyl)-ethylenediaminetrihydrochloride are dissolved in 900 ml. of Water for injection. Thevolume is adjusted to 1000 ml., and the solution is filtered through amedium porosity sintered glass filter. Portions of 1.1 ml. of thefiltrate are filled into glas ampules and sterilized for thirty minutesin an autoclave at pounds steam pressure and at 115.

In the above solution for injuection, the N-(4-picolyl)- ethylenediaminetrihydrochloride may be replaced by any other pharmaceuticallyacceptable acid addition'salt of N-(4-picolyl)-ethylenediamine, as wellas by a pharmaceutically acceptable acid addition salt of N-(2-picolyl)-ethylenediamine or of N-(3-picolyl)-ethylenediamine.

The compounds used as the active ingredients in the above compositionsare prepared as followes (tempertures are given in degrees centigrade):

Example A A solution of 25.0 g. of 4-picolyl chloride hydrochloride in50 ml. of Water is treated with a saturated aqueous soltuion of anequivalent amount of potassium carbonate; the free 4-picolyl chloride,obtained as an oil, is added dropwise to 50.0 g. of ethylenediaminewhile maintaining the temperature below 20. After the addition iscompleted, the reaction mixture is heated on the steam bath for one hourwhile stirring. The excess of ethylenediamine is then distilled off; theresidue is dissolved in 100 ml. of ethanol and an equivalent solution ofpotas sium hydroxide in ethanol is added. The insoluble potassiumchloride is filtered off, and the filtrate is evaporated under reducedpressure. The desired N-(4- picolyl)-ethylenediamine is purified bydistilling the residue and is collected at 95102/ 0.05 mm.; yield. 29.0g.

The flee N-(4-picolyl)-ethylenediamine is dissolved in methanol; amethanol solution of hydrogen chloride is added and the salt isprecipitated by adding diethyl ether. The desiredN-(4-picolyl)-ethylenediamine trihydrochloride melts at 249252 afterrecrystallization from methanol.

Example B The N-(3-picolyl)-ethylenediamine is prepared according to theprocedure described in Example A, by replacing the 4-picolyl chloridehydrochloride with 25.0 g. of 3-picolyl chloride hydrochloride; thedesired N-(3- icolyD-ethyIenediamine is collected at -121/0.7 mm.;yield: 15.0 g.; and is converted into its trihydrochloride as describedin Example A.

Example C By replacing the 4-picolyl chloride hydrochloride with 50.0 g.of 2-picolyl chloride hydrochloride, converting it into the freecompound and reacting the latter with ethylenediamine as described inExample A, the N-(2- picolyl)-ethylenediamine is obtained. It ispurified by distillation, collected at 102-103/0.4 mm.; yield: 13.2 g.;and converted into its trihydrochloride.

What is claimed is:

1. A pharmaceutical composition consisting essentially of apharmacologically effective amount of a member selected from the groupconsisting of a compound of the formula and a pharmaceuticallyacceptable acid addition salt thereof, as the active antihypertensiveingredient, together with a pharmaceutically acceptable carrier.

2. A pharmaceutical composition consisting essentially of apharmacologically effective amount of a member selected from the groupconsisting of N(4-picolyl)- ethylenediamine and a pharmaceuticallyacceptable acid addition salt thereof, as the active antihypertensiveingredient, together with a pharmaceutically acceptable carrier.

3. A pharmaceutical composition consisting essentially of from about 1percent to at most 50 percent by weight of a member selected from thegroup consisting of a compound of the formula and a pharmaceuticallyacceptable acid addition salt thereof, as the active antihypertensiveingredient, together with a pharmaceutically acceptable carrier.

4. A pharmaceutical composition consisting essentially of from about 1percent to at most 50 percent by weight of a member selected from thegroup consisting of N-(4- picolyl)-ethylenediamine and apharmaceutically acceptable acid addition salt thereof, as the activeantihypertensive ingredient, together with a pharmaceutically acceptablecarrier.

5. A pharmaceutical composition for oral use containing as the activeantihypertensive ingredient from about 0.01 g. to about 0.1 g. of amember selected from the group consisting of a compound of the formulaand a pharmaceutically acceptable acid addition salt thereof togetherwith a pharmaceutically accepted carrier, per single dosage unit.

6. A pharmaceutical composition for oral use containing as the activeantihypertensive ingredient about 0.01 g. to about 0.1 g. of a memberselected from the group consisting of N-(4-picolyl)-ethylenediamine anda pharmaceutically acceptable acid addition salt thereof together with apharmaceutically accepted carrier, per single dosage unit.

7. A solution for parenteral administration containing from about 0.01g./ml. to about 0.1 g./ml. of a mem- 7 ber selected from the groupconsisting of a compound of the formula and a pharmaceuticallyacceptable acid addition salt thereof, as the active antihypertensiveingredient together with a pharmacentically acceptable carrier.

8. A solution for parenteral administration containing from about 0.01g./ml. to about 0.1 g./ml. of a member selected from the groupconsisting of N-(4-picolyl)- ethylenediamine and a pharmaceuticallyacceptable acid UNITED STATES PATENTS 5/1956 Szabo et a1 260-501 OTHERREFERENCES Chemical Abstracts, vol. 50, pp. 16849, 91956.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR. Examiner.

MARTIN I. COHEN, Assistant Examiner.

7. A SOLUTION FOR PARENTERAL ADMINISTRATION CONTAINING FROM ABOUT 0.01 G./ML. TO ABOUT 0.1 G./ML. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 